BIOLOGY BASICS

by Roberta Villa


Table of contents

  1. What is Hepatitis?
  2. Why is the liver so important?
  3. What are the causes of Hepatitis?
  4. Which viruses can cause Viral Hepatitis?
  5. How can different viral hepatitis be transmitted and how can transmission be prevented?
  6. Why don’t we have a vaccine for HCV?
  7. Can blood transfusions still transmit HCV nowadays?
  8. What are the challenges of HCV prevention in middle and lower income countries?
  9. What are HCV genotypes, how many strains do we know and how common are they?
  10. What are the symptoms of hepatitis C?
  11. How and how often does hepatitis C evolve?
  12. How can Hepatitis C be diagnosed?
  13. How can the liver damage be assessed?
  14. How can Hepatitis C be treated and managed?

1. What is Hepatitis?

Hepatitis means inflammation of the liver. It can be caused by such things as bacteria, viruses, misuse of alcohol or toxins. Liver inflammation or damage can compromise liver function.

Acute Hepatitis C virus infection is a short-term illness that occurs within the first 6 months after someone is exposed to the Hepatitis C virus. For most people, acute infection leads to chronic infection.

Chronic Hepatitis C virus infection is a long-term illness that occurs when the Hepatitis C virus remains in a person’s body. Hepatitis C virus infection can last a lifetime and lead to serious liver problems, including cirrhosis (scarring of the liver) or liver cancer.

This is because inflammation sustained over an extended period of time leads to liver damage, and repeated attempts to repair the tissue can result in the formation of scars of fibrous tissue.

Liver failure occurs When the liver cannot keep up with the body’s needs anymore, a condition that can be life-threatening and can be cured only by a liver transplant.


2. Why is the liver so important ? What does the liver do?

The liver is a factory

The liver is the largest solid organ in the human body, and performs many vital functions.

It works as a filter between the gut and the rest of the body, but it can also be compared to a factory, which produces, transforms and stores many substances essential to life.

liver damage_timeline_final


The liver

  • filters the blood coming from the gut, processing nutrients, detoxyfying chemicals and metabolizing drugs
  • stops disease causing organisms (is.: bacteria), mainly coming from the intestine, using immune cells residing in the liver
  • controls the levels of fats, amino acids and glucose in the blood
  • produces bile necessary for digestion of food
  • stores iron, copper, vitamins, and other substances essential to the body
  • makes, breaks-down and regulates many hormones
  • manufactures many proteins involved in key processes such as blood clotting or immune response

The liver is organized into two main lobes, which are further subdivided into approximately 100,000 smaller lobes, or lobules, which are the functional structures of the liver – where all its activities are performed.

Liver cells live about 150 days and are very good at regenerating, but if something undermines the lobule’s sophisticated structure, as it happens with scars in cirrhosis, liver function can be compromised


3. What is the most common cause of Hepatitis?

The most common cause of hepatitis is a viral infection. In this case it is called Viral Hepatitis.


4. Which viruses can cause Viral Hepatitis?

We know several viruses that can cause viral hepatitis:

  • hepatitis A virus (HAV): Please refer to table 1 for detailed information about HAV
  • hepatitis B virus (HBV). Please refer to table 1 for detailed information about HBV
  • hepatitis C virus (HCV). Please refer to table 1 for detailed information about HCV

The most important viruses causing hepatitis are Hepatitis A, B and C.

Hepatitis delta virus (HDV) and hepatitis E virus (HEV), are much less common. They are responsible for only 7% of the cases of viral hepatitis in the world.

In some rare cases adenovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), or herpes simplex virus (HSV) can also cause hepatitis.

Table 1

 

Hepatitis D is caused by Hepatitis Delta Virus (HDV). Because HDV needs the hepatitis B virus to replicate and survive in the body, it can only be found in people already infected with HBV.

The HBV vaccine will therefore protect against both infections.

Like other hepatitis viruses, HDV is transmitted through contact with infected blood or blood products, semen, or other bodily fluids.

HDV infection of chronically infected HBV-carriers may lead to fulminant acute hepatitis, a condition in which the liver produces a severe acute inflammatory response leading to extensive tissue damage and liver failure. It is 10 times more likely that fulminant acute hepatitis will develop in individuals co-infected with HDV and HBV than with other types of hepatitis viruses. It is also more likely for HDV/HDV co-infection to lead to severe chronic active hepatitis, increasing the risk of cirrhosis. Worldwide, more than 10 million people are infected with HDV, with a mortality rate between 2% and 20%, which is ten times higher than for hepatitis B alone.

Hepatitis E is caused by Hepatitis E Virus, which infects about 20 million people in the world every year, leading to about 3 million cases of acute hepatitis.

It is transmitted mainly through contaminated drinking water worldwide, and is more common in East and South Asia. It usually resolves within 4–6 weeks, but in some cases can lead to a fulminant form of hepatitis, responsible for 56,600 deaths in the world every year.

The first vaccine to prevent hepatitis E virus infection has been produced and licensed in China, but is not yet available globally.


5. How can different viral hepatitis be transmitted and how can transmission be prevented?

Hepatitis A is transmitted through ingestion of microscopic amounts of fecal material, such as through contaminated food, drink, and objects.

Hepatitis A transmission happens mainly by:

  • eating fruits, vegetables, or other foods contaminated during handling
  • eating raw shellfish harvested from contaminated water
  • swallowing contaminated ice.

These at-risk behaviours should be avoided to prevent transmission, particularly when travelling to countries that have a high or intermediate prevalence of the disease.

Vaccination is the most effective way to prevent Hepatitis A.

Hepatitis B is transmitted by contact with infected blood, semen, or other body fluids.

Hepatitis B transmission can therefore happen by:

  • being born to an infected mother
  • having sexual intercourse with an infected person
  • sharing contaminated needles, syringes, or other injection drug equipment
  • being accidentally pricked by contaminated needlesticks or other sharp instruments (i.e healthcare professionals).

Preventative measures established for other blood and sexually transmitted diseases, both in healthcare and in everyday life, should be adopted to prevent Hepatitis B transmission.

Like Hepatitis A, the most effective way to prevent Hepatitis B is vaccination.

Hepatitis C is spread through blood-to-blood contact. Hepatitis C is not spread through breast milk, food or water. Nor is it spread through casual contact, such as hugging, kissing and sharing food or drinks with an infected person.

Infection can happen by:

  • sharing contaminated needles, syringes, or other injection drug equipment
  • being accidentally pricked by contaminated needlesticks or other sharp instruments (i.e healthcare professionals)
  • having received a blood transfusion or organ transplant before the early 1990s in developed countries — when widespread screening for HCV was introduced with increasing levels of efficacy at detecting the virus. In low resource countries, blood safety remains an issue of major concern.

Birth to an infected mother is a less common mode of transmission. According to US Centers for Disease prevention and Control (CDC), approximately 6% of infants born to infected mothers will get Hepatitis C.

HCV infection can only be prevented by avoiding blood-to-blood contacts.

Preventative measures should also include getting tattoes and piercings in certified facilities that use sterile instruments. Healthcare workers should follow professional preventative guidelines.

HCV cannot usually be transmitted sexually. Nevertheless, even if sexual transmission is very uncommon, practices involving blood contact should be considered at risk behaviors. Having a sexually transmitted disease or HIV, having sex with multiple partners, or engaging in rough sex appears to increase a person’s risk of getting Hepatitis C.

Sharing razors and toothbrushes can expose an individual to infection as well.

Still, about 1 out of 4 patients does not know how or when he or she was infected.

People who have recovered from acute hepatitis C and those who have been cured must be careful about prevention, since reinfection is possible.

There is as yet, no proven vaccine for HCV.


6. Why don’t we have a vaccine for HCV?

A vaccine contains a biological agent that is usually an attenuated or replication-deficient version of a disease causing organism. Exposure to this agent will safely stimulate an individual’s immune system to acquire an immunity to the microorganism without causing disease. HCV is a difficult virus to produce a vaccine for because of its genetic diversity. As such, it is a challenge for scientists to find a target on the virus that is common across HCV genotypes and subgenotypes.

In contrast, HBV is easily recognized by the protein called Antigen Australia (HBsAg), and an immunological response against HbsAg can stop the infection, but researchers have not yet found such a promising target in the structure of HCV.

The first vaccine for HCV to reach clinical trials was found to be safe and produced a good immune response in the 15 healthy human volunteers who took part in the phase 1 safety trial. Its efficacy is currently under investigation among intravenous drug users in two sites in the USA.


7. Can blood transfusions still transmit HCV today?

In developed countries, the first blood test for HCV was introduced in 1990. This test could detect antibodies against HCV proteins. In the USA, screening blood from donors with this HCV test decreased the risk of transfusion-associated HCV infection per unit of blood from 0.36% (1 in 274) to 0.07% (1 in 3300). Today it is estimated that this test has prevented transmission of HCV to 40,000 patients per year in the US. This test wasn’t perfect. Antibodies to HCV weren’t detectable in the blood for at least 12 weeks after infection, and sometimes more than 26 weeks. During this window, tainted blood could therefore appear safe.

A second-generation more sensitive test, able to detect infected blood as early as 10-20 days post infection, was developed and approved in 1992 . It is estimated that this new test prevented an additional 13,000 people from becoming infected with HCV each year.

history of postransfusion hepGlobally, blood transfusions are not yet as safe as they are in higher-income countries. Of 148 countries that provided WHO data for screening, 41 reported that they lacked the resources to screen all donated blood for one or more of the required transfusion-transmitted diseases (HIV, hepatitis B, hepatitis C, syphilis).

In sub-Saharan Africa, 28 out of the 40 countries have yet to implement national quality systems needed to assure effective screening of donated blood. WHO estimates that the lack of effective screening results in up to 5 million new infections of hepatitis C every year in the world.


8. What are the challenges of HCV prevention in lower income countries?

The transmission of hepatitis C persists in most parts of Africa, as well as in other parts of the world, primarily because of traditional habits and a lack of resources in healthcare settings.


 9What are HCV genotypes, how many strains do we know and how common are they?

There are 7 main genotypes of Hepatitis C . These differences are based on major viral genetic characteristics, i.e. differences in the genetic sequence that may affect functional features of the virus and how it will respond to pharmacological treatments or antiviral drugs like interferon.

Other, more minor, variants can be found within each genotype; HCV is further classified into 67 confirmed and 20 provisional subtypes. The genetic differences between subtypes are more subtle, but these still need to be considered since these can sometimes influence the virus’s response to different kinds of treatments . In genotype 1, for example, the difference between genotype 1a and 1b is relevant in terms of anticipated treatment response and must therefore be assessed before initiating treatment.

The high degree of genetic diversity of HCV continues to pose a significant challenge for achieving successful vaccines and drug therapies that are effective for all genotypes and subtypes, the so-called pan-genotypic treatment. Such an option would be of particularinterest in developing countries, where genotype testing is often unreliable or difficult to perform.

most common genotypes

Some current treatments are said to be pan-genotypic, but in the real world they have different degrees of effectiveness for different genotypes and are not approved for all of them (see treatment module). Doses, length of treatment, and rate of success still partly depend on HCV genotype, and sometimes subtype. Alternative drugs with broader efficacy are currently under investigation.

It is possible for a person to be infected with more than one genotype.

Globally, the most common genotype is G1 (42% of all HCV cases), followed by G3 (26%) and G4 (17%). The most common subtype is 1b (27%).

 Global distribution of different genotypes shows different prevalence in different areas of the world.

prevalence map_genotypes

Map taken from Messina et al, 2014 (Fig 1A)

Genotype 1 (subtype 1b), is the most prevalent genotype in higher income countries, followed by genotype 3.

The global distribution of HCV genetic variation could be related to historical and contemporary trends in human migration. For example, strains from West Africa (genotype 2) could have been brought to the Americas through the trans-Atlantic slave trade.

One possible explanation for the global distribution of genotype 1 is its association with the most common cause of HCV infection in the 20th century — the distribution of contaminated blood and blood products before HCV screening of blood began. In fact, genotype 1 is prevalent in developed countries, where blood transfusions were more available and widespread: a hypothesis is that the most common sources of blood in those years were from areas where this genotype was prevalent.

The global dissemination of genotype 3 is more likely to be attributed to the association of subtype 3a with injection drug use and to population migration in United Kingdom during colonialism from countries where subtype 3a is dominant, such as India and Pakistan.

Even if genotype 1 and 3 infections are more prevalent than all other genotypes globally. Genotypes found more commonly in lower-income countries still account for a significant proportion of HCV cases worldwide. Specifically, genotype 2 is most frequent in West Africa and parts of South America (the latter likely reflecting population movements resulting from the trans-Atlantic slave trade), while genotypes 4 and 6 are common in Central/North Africa and East/Southeast Asia, respectively.

be aware box_1


10. What are the symptoms of hepatitis C?

Most people with hepatitis C do not have symptoms and do not know they are infected until their liver has sustained significant damage.

A chronic viral hepatitis infection can present without any symptoms for decades.
However, it is possible to experience the following symptoms:

  • feeling unusually tired all the time
  • depression
  • jaundice
  • a general sense of feeling unwell
  • abdominal pain or bloating
  • loss of memory
  • itchy skin

Since these symptoms are very vague, and similar to those reported in many other common diseases, people are often unaware of their condition until they develop cirrhosis, when scar tissue replaces healthy tissue in the liver and prevents the liver from working properly.

The early stages of cirrhosis can be as insidious as the previous phases, with very few or no symptoms experienced by the individual, but as the liver loses its ability to function properly, a loss of appetite, nausea and itchy skin become more and more common.
As the disease progresses, and liver functions are affected, many new symptoms tend to develop:

  • weight loss and muscle wasting
  • tenderness or pain around the liver area
  • blood capillaries on the skin above waist level
  • a tendency to bleed and bruise more easily, such as frequent nosebleeds or bleeding gums
  • hair loss
  • fever and shivering attacks
  • swelling in the legs, ankles and feet due to a build-up of fluid (edema)
  • swelling in abdomen, due to a build-up of fluid known as ascites

Changes in personality, insomnia, memory loss, confusion and difficulty concentrating are caused by an encephalopathy that can occur when toxins affect the brain, because the liver is unable to remove them from the body.


11. How often does the disease progress into a chronic infection and what happens to the liver?

According to the WHO, at least 15% of infected persons spontaneously clear the virus within 6 months of infection, without any treatment.

The remaining 55–85% of persons will develop a chronic HCV infection. When chronic Hepatitis C develops, it can result in long-term health problems, including liver damage, liver failure, liver cancer, and even death.
Of those with chronic HCV infection, the risk of cirrhosis of the liver is 15–30% within 20 years.
Chronic hepatitis C is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplantation in the United States.

For every 100 persons infected with HCV, approximately 1–5 will die from the consequences of chronic infection (liver cancer or cirrhosis) (source CDC).

liver damage_timeline_final

based on http://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/natural-history/core-concept/all


12. How can Hepatitis C be diagnosed?

In most cases infection is identified when the patient is screened for blood donation or when elevated alanine aminotransferase (ALT, a liver enzyme) levels are detected during routine medical exams.

When HCV infection is suspected, a blood test is performed to search for antibodies against HCV. If the test detects the presence of antibodies, a second test is performed to directly establish whether the virus itself is currently present in the individual.

org chart_good one2

The diagnosis of chronic hepatitis C is based on the detection of both anti-HCV antibodies and direct detection of the HCV virus in the presence of biological (i.e. abnormal levels of liver enzymes in blood tests) or histological (that can be seen examining small parts of liver tissue taken by biopsy) signs of chronic hepatitis.

Having anti-HCV antibodies (anti-HCV positive) in blood does not necessarily mean that an individual has an active hepatitis C infection. The presence of antibodies is an indication that a person has at some point in the past mounted an immune response againt HCV. Approximately 20% of the infected people clear the virus within 6 months, and these individuals will continue to carry antibodies againt HCV. Anti-HCV-positive, HCV RNA negative individuals should be retested for HCV RNA three months later to confirm true convalescence. After that, they are not considered to have hepatitis C. Although no longer infected, they will still test positive for anti-HCV antibodies all their lives. Since they don’t host the virus in their blood, they cannot spread the disease.

However, the presence of both anti-HCV antibodies and the HCV virus in blood indicates the presence of a hepatitis C infection and, consequently, that the person is infectious. If the direct HCV test is negative within 6 months, the patient had acute hepatitis C. If the test continues to yield positive results beyond 6 months, the patient is diagnosed with chronic hepatitis C.

After that time, it is very rare for the immune system to clear the virus and for the test to be negative.

Unfortunately, HCV antibodies are not protective against reinfection, which can occur after successful treatment as well (See Treatment module for more information).

Table 2A laboratory test for identifying the genotype (and 1a/1b subtype) of the hepatitis C strain and an assessment of liver damage will guide treatment choices.

Establishing the amount of virus present, or the “viral load” can also help predict a treatment’s success.

A test of the patient’s DNA can help determine how effective certain drugs can be against HCV. Variants of a gene involved in the immune response against HCV (Interleukin 28B, IL28B), can alter the effect of certain HCV treatments (See Treatment module).


13. How can liver damage be assessed?

One of the main factors influencing the type and timing of treatment is the severity of liver disease.
Patients with cirrhosis have to be identified since their treatment regimen needs to be adapted accordingly. The fibrosis stage can be assessed initially with imaging (ultrasound scan, MRI,…), liver stiffness measurement, and identification of biomarkers in the blood.

Liver stiffness measurement (FibroScan®) measures how quickly vibrations pass through the liver. The more ‘stiff’ or damaged the liver is, the more quickly the waves will pass through it .

Blood biomarkers include several direct markers which correlate with, or are part of, the liver matrix that is produced in the fibrosis process. Other indirect markers reflect changes in liver function. They are molecules released into the blood when there is inflammation of the liver.

Both stiffness measurement and biomarkers can distinguish quite well between cirrhosis and no-fibrosis. Combined, these tests can identify intermediate degrees of fibrosis. These tests reduce the need for an invasive liver biopsy, a procedure that can be problematic for patients with impaired blood clotting capacity.
In patients without compromised blood clotting, there is little risk of hemorrage from a liver biopsy, since it involves taking a small tissue sample from the liver though the skin by percutaneous core needle, under ultrasound guide. This tissue sample is then examined under a microscope.


14. How is Hepatitis C treated and managed?

When a diagnosis of Hepatitis C is confirmed, the presence or absence of other diseases must be established since this can influence prognosis and treatment. Mycotoxins, as well as alcohol, can make the evolution of the disease more severe. A concurrent infection with HIV, for example, can require a different approach with different drugs, and possible drug interactions must also be considered.

The degree of liver damage and virus genotype are used to drive treatment and management of the disease (see treatment module).

A therapy’s success is evaluated by blood tests showing no detectable virus. A sustained virus response (SVR), is the continued absence of detectable HCV virus in the blood six months (24 weeks) after the end of treatment.

The antiviral Interferon-α was the the first drug treatment for HCV after it was discovered in 1989. In 2011, a more persistent form of interferon-α (Pegylated interferon- α), together with the antiviral drug ribavirin, increased the rates of success. These, however, never exceeded a 50% cure rate, and their heavy side effects often forced patients to discontinue the treatment.

In 2011, new antivirals called Direct Agent Antivirals (DAA, i.e. protease inhibitors acting directly on the virus instead of on the patient) were introduced, to be given in association with previous drugs (triple therapy regimen). They improved the SVR in up to 75% of patients, but with even worse side effects.

All these therapies were more effective on other genotypes than on genotype 1, the most common in higher income countries. Substantial research efforts led to a new class of DAA. The first to be introduced was sofosbuvir in 2014. The new therapies are even more effective on genotype 1 than on others, approaching 95% of success rates in clinical trials with fewer and milder side effects.
Now, the real challenge is providing access to these revolutionary drugs (please refer to Treatment section for success rates of the DAA in other genotypes). They are very expensive and on a global scale most healthcare systems and patients cannot afford them.

This has made hepatitis C therapy more a policy issue than a medical one.


REFERENCES

Prati, D. Transmission of hepatitis C virus by blood transfusions and other medical procedures: a global review. J Hepatol 2006; 45:607-16.

Pondè RA Hidden hazards of HCV transmission. Medical Microbiology and Immunology. 2011; 200:7-11

Swadling L et al. Science Translational Medicine 2014; 261, 261
DOI: 10.1126/scitranslmed.300918

http://www.clinchem.org/content/43/8/1487.full

http://www.who.int/bloodsafety/ImprovingBloodSafetyWorldwide.pdf?ua=1http://www.who.int/bloodsafety/ScreeningDonatedBloodforTransfusion.pdf

Messina J et al. Global Distribution and Prevalence of Hepatitis C Virus Genotypes. Hepatology, 2014

EASL Recommendations on Treatment of Hepatitis C 2015.
European Association for the Study of the Liver (EASL). Journal of Hepatology, May 2015

http://www.hindawi.com/journals/ahe/2014/357287/ Advances in Hepatology
Volume 2014 (2014), Article ID 357287 April 2014. H. Fallatah. Review Article: Noninvasive Biomarkers of Liver Fibrosis: An Overview.

Who http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index5.html